Abstract
Myristoylated alanine-rich C kinase substrate-like 1 (MARCKSL1) plays a pivotal role in the regulation of apoptosis and has been shown to maintain antitumor and metastasis-suppressive properties. In the present study, we examined the effects of MARCKSL1 as a novel anti-angiogenic agent on the inhibition of angiogenesis-mediated cell migration. MARCKSL1 also reduced vascular endothelial growth factor (VEGF)-induced human umbilical vein endothelial cell (HUVEC) proliferation, as well as capillary-like tubular structure formation in vitro. MARCKSL1 disrupted phosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) in ovarian tumorigenesis. In addition, MARCKSL1 showed potent anti-angiogenic activity and reduced the levels of VEGF and hypoxia-inducible factor 1α (HIF-1α) expression, an essential regulator of angiogenesis. Consistently, MARCKSL1 decreased VEGF‑induced phosphorylation of the PI3K/Akt signaling pathway components, including phosphoinositide-dependent protein kinase 1 (PDK-1), mammalian target of rapamycin (mTOR), tuberous sclerosis complex 2 (TSC-2), p70 ribosomal protein S6 kinase (p70S6K), and glycogen synthase kinase 3β (GSK-3β) protein. Collectively, our results provide evidence for the physiological/biological function of an endothelial cell system involved in angiogenesis through suppression of Akt/PDK-1/mTOR phosphorylation by interaction with VEGFR-2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calmodulin-Binding Proteins
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Cell Line, Tumor
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Cell Movement
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Endothelial Cells / physiology*
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Female
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Glycogen Synthase Kinase 3 / biosynthesis
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 beta
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Human Umbilical Vein Endothelial Cells
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Microfilament Proteins
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Neovascularization, Pathologic / physiopathology*
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Ovarian Neoplasms / pathology
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Phosphorylation / physiology
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Protein Processing, Post-Translational / physiology*
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Recombinant Fusion Proteins / metabolism
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Ribosomal Protein S6 Kinases, 70-kDa / biosynthesis
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Ribosomal Protein S6 Kinases, 70-kDa / genetics
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Signal Transduction / physiology*
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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Transfection
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins / biosynthesis
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Tumor Suppressor Proteins / genetics
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Two-Hybrid System Techniques
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Substances
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Calmodulin-Binding Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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MARCKSL1 protein, human
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Membrane Proteins
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Microfilament Proteins
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Neoplasm Proteins
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Recombinant Fusion Proteins
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Tuberous Sclerosis Complex 2 Protein
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Tumor Suppressor Proteins
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MTOR protein, human
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KDR protein, human
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Vascular Endothelial Growth Factor Receptor-2
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AKT1 protein, human
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases, 70-kDa
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TOR Serine-Threonine Kinases
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Glycogen Synthase Kinase 3